Gonadal steroids are among the numerous factors influencing food intake and body weight in mammals. Hormonal effects on these processes are particularly striking in female rats, which show large increases in food intake and body weight after ovariectomy (Wade, 1975). A key role of estrogen in the control of food intake and energy balance in humans is evidenced by the fact that the incidence of obesity increases greatly after menopause (American College of Obstetricians and Gynecologists, 2005). The actions of estradiol on neural systems that regulate eating may also account in part for sex differences in food intake and eating disorders, which occur much more frequently in young women (Sodersten &Bergh, 2003). Although the effects of estradiol on food intake appear to be mediated in part by interactions with CCK systems that participate in the control of meal size (Butera et al., 1993;Geary et al., 1995), the observation that CCK antagonists do not completely reverse the anorectic action of estradiol indicates that CCK is not the only factor involved mediating the reduction in feeding caused by estrogen (Eckel &Geary, 1999). Along these lines, ghrelin is a peptide hormone synthesized principally in the stomach that binds to a receptor in the brain and regulates growth hormone secretion. Studies in humans and rodents indicate that ghrelin levels increase prior to a meal and that ghrelin treatment increases food intake in male rats (Beck et al., 2002;Cummings &Schwartz, 2003). Several lines of evidence indicate that ghrelin production, secretion, and its effects on behavior and metabolism are influenced by estrogen (Matsubara et al., 2004;Kemp et al., 2005). These data suggest that interactions between ghrelin and estradiol may underlie the inhibitory effects of estradiol on feeding behavior and the weight gain caused by ovariectomy and estrogen withdrawal. The general goals of the first two experiments in this AREA grant proposal are to examine the effects of ghrelin on food intake and meal patterns in female and male rats and evaluate the ability of estrogen to modulate the appetite-stimulating effects of ghrelin. Examining changes in the microstructure of ingestive behavior will provide a better understanding of the ways in which estradiol and ghrelin interact with neurobiological controls of food intake (Smith, 2000). The third experiment will evaluate the ability of estradiol to influence the central processing of the ghrelin signal by examining the effects of estradiol on ghrelin-induced c-Fos expression in the brains of female rats. Information obtained from these experiments will contribute to our understanding of mechanisms involved in the control of food intake and provide additional information on the mechanisms by which ovarian hormones affect eating and contribute to sex differences in food intake. The ability of estrogen to interact with orexigenic signals like ghrelin may also shed light on the factors associated with menopause and obesity as well as potential causes of sex differences in eating disorders. - Human Health Significance In this revised application I have discussed the ways in which the proposed research has significance for human health and disease and how the proposed studies can improve our understanding of the role of estrogen in the development of weight gain and obesity in postmenopausal women, mechanisms underlying sex differences in food intake, and the endocrine basis of eating disorders that can contribute to the large sex difference in the prevalence of anorexia and bulimia nervosa.